tbuckley/cabot-search huggingface dataset:
Abstract 3930: MCT1 as a potential target in the progression of oral premalignant dysplasia to invasive squamous cell carcinoma
Authors: Ethan J. Wong, Ali Khammanivong, Ravi Maisuria, Erin B. Dickerson, Raj Gopalakrishnan
Journal: Cancer Research (2023)

Abstract Introduction: Most oral squamous cell carcinomas (OSCC) progress through clinically identifiable stages, starting from premalignant epithelial dysplasia to early invasive OSCC. How cells transform from premalignant dysplasia to early invasive OSCC is unknown. High monocarboxylate transporter 1 (MCT1; SLC16A1) expression is correlated with poor outcomes in OSCC patients, where it is thought to promote tumor growth by supporting metabolic coupling between cancer cells and tumor stroma. Because expression of MCT1 is markedly increased in OSCC patients, we sought to determine if MCT1 played a role in the progression of oral dysplasia in early invasive OSCC. Methods: Immunohistochemistry (IHC) was used to evaluate changes in the levels of MCT1 expression across adjacent normal, dysplasia, and OSCC tissues to identify expression patterns during cancer progression. Genetic knockout (KO) of SLC16A1 via CRISPR/Cas9 and pharmacological blockade by the MCT1 inhibitor AZD3965 were used on OSCC (TR146) and dysplastic (DOK) cell lines. KO was confirmed by qRT-PCR and immunoblotting. MCT1-KO and AZD3965-treated cells were assayed for changes in cell invasion using Matrigel-coated transwell assays. Correlative changes in gene expression based on MCT1 staining and disease progression were also observed in adjacent normal, dysplasia, and OSCC regions in each tissue section using Nanostring GeoMx Digital Spatial Profiler. Results: Expression of MCT1 was directly correlated to the progression of disease from dysplasia to early superficially invasive OSCC relative to normal adjacent epithelium. KO of MCT1 significantly decreased the invasion of dysplastic and OSCC cell lines compared to the wild-type (parental) controls. AZD3965 also decreased invasion in the parental dysplastic and OSCC lines. To identify progressive changes in gene expression across normal, dysplasia, and early invasive OSCC, transcripts for cancer-related genes were quantified in the epithelial and stromal compartments from patient samples. Compared to the normal epithelium, upregulation in gene expression, including SLC16A1, was observed in the cell cycle and metabolic pathways in OSCC tissues. Conclusions: Our data suggest that MCT1 plays a key role in breaching of the basement membrane and facilitating tumor cell migration and invasion. Targeting MCT1 in oral dysplasia may prevent progression to OSCC in oral cancer patients. Citation Format: Ethan J. Wong, Ali Khammanivong, Ravi Maisuria, Erin B. Dickerson, Raj Gopalakrishnan. MCT1 as a potential target in the progression of oral premalignant dysplasia to invasive squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3930.
Abstract 3184: Single-cell analysis of CAR T-cells helps uncover distinct functional signatures following CAR T-cell manufacturing
Authors: Alfredo Sebastian Colina, Ravi Shah, Tanya Kozlik, Michael B. Dwinell, Bryon Johnson, Nirav Shah, Anthony Zamora
Journal: Cancer Research (2023)

Abstract Chimeric antigen receptor T cell (CAR-T) therapy has proven a major success for patients with B cell malignancies. Despite recent advancements, some patients never mount an effective antitumor response and ultimately succumb to their disease. While modifications to specific CAR construct domains have resulted in greater CAR-T expansion and functional responses in some patients, it has become increasingly evident that more studies are needed to evaluate the impact of intra- and inter-patient functional heterogeneity on clinical efficacy. To begin deciphering the factors governing these disparate functionalities, we performed single-cell polyfunctional assessments of bispecific CD20/CD19 CAR-T cells and accounted for how differences in their manufacturing could further alter functional capacity. Based on our preliminary data, we hypothesized that differences in CAR-T’s underlying biology, such as their phenotypic, transcriptional, and functional status, mediate their persistence, cytotoxicity, and clinical efficacy. By taking advantage of BLI’s Lightning platform, which interrogates and links CAR-T’s cytotoxic function, secretory profile, and transcriptional state at single-cell resolution, we uncovered key manufacturing processes that alter CAR-T cell antitumor function. We’ve also identified distinct immune signatures associated with clinical response. Future studies will utilize in vivo mouse tumor models to validate the immunological signatures driving CAR-T cell functionality and persistence after infusion. Our studies suggest that differences in CAR T-cell manufacturing protocols alter the immunological signatures of T cells, which can be exploited to guide future therapeutic interventions and the design of future clinical trials. Citation Format: Alfredo Sebastian Colina, Ravi Shah, Tanya Kozlik, Michael B. Dwinell, Bryon Johnson, Nirav Shah, Anthony Zamora. Single-cell analysis of CAR T-cells helps uncover distinct functional signatures following CAR T-cell manufacturing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3184.
Abstract 3949: CYR61, a member of the CCN protein family, regulates IGF-1 in metastatic prostate cancer
Authors: Greisha L. Ortiz-Hernandez, Mya Walker, Leanne Woods-Burnham, Rick A. Kittles, Carlos A. Casiano, Susan L. Neuhausen
Journal: Cancer Research (2023)

Abstract The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. Interestingly, CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF-1). High serum levels of IGF-1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF-1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. This study is designated to specifically determine and characterize the molecular interaction between CYR61 and IGF-1 in metastatic PCa and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3 and downregulated in the docetaxel-resistant cell line PC3-DR. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF-1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. We also initiated studies to determine the co-localization of CYR61 and IGF-1 using immunofluorescence microscopy (IF). Based on the initial IF observations, we will proceed to examine if their interaction is primarily intra- or extra-cellular. For intracellular interactions, we will co-immunoprecipitate CYR61 with IGF-1 and for extracellular interactions, we will use the AVidity-based EXtracellular Interaction Screen (AVEXIS) system. Our goal is to establish the contribution of CYR61-IGF1 protein-protein interaction to PCa cell proliferation. Specifically, the correlation between PCa aggressiveness and circulating levels of CYR61 and IGF-1 is poorly studied. Their combined role may explain a proportion of aggressive PCa. Citation Format: Greisha L. Ortiz-Hernandez, Mya Walker, Leanne Woods-Burnham, Rick A. Kittles, Carlos A. Casiano, Susan L. Neuhausen. CYR61, a member of the CCN protein family, regulates IGF-1 in metastatic prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3949.
Abstract 3189: Pre-clinical evaluation of novel folate receptor 1 directed CAR T cells for high grade serous ovarian cancer
Authors: Christoph Herbel, Julie Daigre, Manuel Martinez-Osuna, Maria Bethke, Larissa Steiner, Janina Brauner, Jens Kopatz, Paurush Praveen, Dominik Eckardt, Andreas Bosio
Journal: Cancer Research (2023)

Abstract Purpose: Treatment of ovarian cancer remains challenging. A high unmet clinical need for targeted, efficient, and persisting drugs still is a major issue for clinicians and patients diagnosed with ovarian cancer, particularly platinum-resistant and-refractory, recurrent disease. Genetically modified T cells expressing chimeric antigen receptors (CARs) have shown efficient, as well as persisting anti-tumor functionality in hematological malignancies. However, solid cancers have not yet been as efficiently treated with CAR T cells, potentially due to the lack of appropriate targets. Therefore, we thoroughly characterized FOLR1 as CAR T cell target for ovarian cancer, designed novel CAR T cells, and assessed these drug candidates preclinically in vitro and in vivo. Experimental Design: We performed ultra-high content imaging on high-grade serous epithelial ovarian cancer as well as healthy tissue samples to profile the expression of the tumor-associated antigen FOLR1. Subsequently, we designed a series of CAR T cell candidates based on different monoclonal antibodies targeting FOLR1, in order to leverage on clinical experience with these binders, particularly safety aspects. The CAR designs differed in the VL-VH orientation and the spacer domain of the CAR construct. The preclinical assessment of various FOLR1-directed CAR T cell constructs was evaluated against various ovarian cancer cell lines in vitro and in vivo. Results: In this study we show high and consistent expression of the tumor-associated antigen FOLR1 on primary ovarian cancer samples, namely high-grade serous ovarian cancer. Moreover, FOLR1 expression is low, restricted, and polarized in healthy tissues. We generated diverse FOLR1-specific CAR T cells and characterized their efficacy and specificity in vitro as well as in an ovarian cancer xenograft model. CAR T cells rapidly and efficiently eradicate xenograft tumors. This anti-tumor response is accompanied by CAR T cell expansion, FOLR1-dependent cytokine secretion, and infiltration of CAR T cells into the tumor. Conclusions: These findings demonstrate the feasibility of a preclinical CAR T cell approach targeting FOLR1 as treatment option for ovarian cancer and potentially other FOLR1-expressing tumors. Citation Format: Christoph Herbel, Julie Daigre, Manuel Martinez-Osuna, Maria Bethke, Larissa Steiner, Janina Brauner, Jens Kopatz, Paurush Praveen, Dominik Eckardt, Andreas Bosio. Pre-clinical evaluation of novel folate receptor 1 directed CAR T cells for high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3189.
Abstract 4037: Doxazosin exerts anti-metastatic potential in triple-negative breast cancer via impairment of cancer stem-like features
Authors: Seongjae Kim, Dongmi Ko, Juyeon Seo, Soeun Park, Minsu Park, Kee Dal Nam, Yong koo Kang, So Ra Seock, Jaeyoun Park, Eunhye Oh, Eunsun Jung, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo
Journal: Cancer Research (2023)

Abstract Background and Purpose: Triple-negative breast cancer (TNBC) tumors typically harbor a high cancer stem-like population leading to chemo-resistance, recurrence, and metastasis. Tumor metastasis is associated with 90% of cancer-related deaths, highlighting the urgent clinical unmet need. Doxazosin is known to inhibit cell migration and invasion in several cancer cell types; however, the precise mechanisms underlying doxazosin’s anticancer effects in TNBC have not been fully elucidated. In the present study, we sought to investigate the mechanism of action of doxazosin responsible for its effects on apoptosis, cancer stem cell (CSC)-like properties, cell migration, and metastasis in TNBC. Experimental designs: Doxazosin on TNBC cell lines [MDA-MB-231, BT549, and 4T1] in vitro was evaluated in cell viability, apoptosis, cell migration, CD44/CD24 staining, ALDH1 activity, and mammosphere formation. The effect of doxazosin on tumor growth, angiogenesis, and metastasis was evaluated in an orthotopic allograft mice model with CSC-enriched population. Results: Doxazosin significantly reduced cell viability and induced apoptosis in MDA-MB-231 and BT549 cells via activation of caspase-3/-7 and cleavage of PARP. Doxazosin significantly suppressed cell migratory capability, concomitant with disrupting cytoskeletal proteins, including vimentin and F-actin expression in TNBC cells. An impairment of BCSC-like properties was associated with reduction of ALDH1 activity and the CD44+/CD24- population, concomitant with suppression of mammosphere-forming ability. Doxazosin administration reduced tumor growth and lung metastasis, as evidenced by a sharp decline in bioluminescence signal intensity. Inhibitory effect of tumor growth was accompanied by a significant decrease of Ki-67 and enhancement of apoptosis with DNA fragmentation and increased cleaved-caspase-3 expression. The latter phenomenon was associated with the impediment of JAK2/STAT3 signaling pathway and CSC-like properties. Furthermore, no toxic effects of doxazosin were found in liver and kidney function in animals. Conclusion: Taken together, our findings highlight doxazosin as a promising candidate for drug repurposing in suppressing metastatic TNBC. Citation Format: Seongjae Kim, Dongmi Ko, Juyeon Seo, Soeun Park, Minsu Park, Kee Dal Nam, Yong koo Kang, So Ra Seock, Jaeyoun Park, Eunhye Oh, Eunsun Jung, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. Doxazosin exerts anti-metastatic potential in triple-negative breast cancer via impairment of cancer stem-like features. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4037.
Abstract 3188: Patient-derived TAC01-HER2 TAC T cells produced in Cocoon® Platform is highly functional in models of solid tumors
Authors: Ling Wang, Stacey X. Xu, Tania Benatar, Ritu R. Randhawa, Philbert Ip, Prabha Lal, Thanyashanthi Nitya-Nootan, Laura Ravensbergen, Heather MacGregor, Suzy Prosser, Sadhak Sengupta, Christopher W. Helsen, Andreas G. Bader
Journal: Cancer Research (2023)

Abstract Background: The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the re-direction of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex with the goal to elicit a safe and durable anti-tumor response. TAC01-HER2, a first-in-class TAC T product targeting HER2 (ERBB2), has entered a Phase I/II clinical trial in patients with HER2-positive solid tumors. Here, we characterized the TAC T cell phenotypes and anti-tumor activity of TAC01-HER2 manufactured using leukocytes from Phase I/II patients in nonclinical in vitro and in vivo assays. Materials and Methods: TAC T cell proliferation, activation, and phenotype of patient-derived TAC01-HER2 were assessed by flow cytometric analysis. In vitro anti-tumor cytotoxicity was assessed via a real-time microscopy-based co-culture assay, and in vivo anti-tumor activity of TAC01-HER2 was assessed in mice engrafted with established solid HER2-expressing human tumors. Results: Complex phenotype analysis showed that patient-derived TAC01-HER2 products consisted of a high percentage of memory T cells similar to products generated from healthy donors. Patient-derived products had significant proportions of CD4 and CD8 T cells, with CD4 being the predominant population in several of these. In a 5-day in vitro potency assay, patient-derived products showed effective tumor cell killing at low E:T rations (1:1 to 1:20) which was comparable to product generated from healthy donors. Similarly, intravenous administration of patient-derived TAC01-HER2 in mice carrying HER2-positive tumors xenografts led to a complete and sustained tumor clearance. Conclusion: The in vitro and in vivo data confirm the potency of patient-derived TAC01-HER2 against HER2-expressing solid tumor models. This work combined with other biomarkers may help correlate nonclinical potency with clinical outcomes. Citation Format: Ling Wang, Stacey X. Xu, Tania Benatar, Ritu R. Randhawa, Philbert Ip, Prabha Lal, Thanyashanthi Nitya-Nootan, Laura Ravensbergen, Heather MacGregor, Suzy Prosser, Sadhak Sengupta, Christopher W. Helsen, Andreas G. Bader. Patient-derived TAC01-HER2 TAC T cells produced in Cocoon® Platform is highly functional in models of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3188.
Abstract 3947: S100A8/A9-RAGE pathway and chronic airway inflammation in cigarette smoke-induced lung carcinogenesis
Authors: Hye Seon Kang, In Kyoung Kim, Chang Dong Yeo, Jin Woo Kim, Sang Haak Lee
Journal: Cancer Research (2023)

Abstract Background: Cigarette smoke-induced chronic airway inflammation increases the risk of lung cancer, and plays a multifaceted role in lung cancer initiation and progression, and RAGE-ligand axis (HMGB1, S100A8/A9) contributes Cigarette smoke-induced persistent and progressive inflammation. The aim of the present study was to determine the inflammatory effect on S100A8/A9-RAGE pathway in smoke-induced carcinogenesis in lung cancer. Methods: Human alveolar adenocarcinoma cells (A549) and normal bronchial epithelial cells (BEAS-2B) were co-cultured for 24 h with the PBMC and then, cells were incubated in the presence or absence of 1.5% cigarette smoke extract (CSE) for 24 h. The cells transfected with siRNA targeting S100A8/9 or RAGE. The cell viability, colony-forming ability, migration, invasion, metastasis and morphological changes were assessed. Female A/J mice were given a benzo(a)pyrene (100mg/kg) in 0.1 ml corn oil via oral gavage at once a week for 3 weeks, and administrated CSE (1.25 ul/g) via intratracheal (IT) at twice a week for 4 weeks. Tumor load was determined by averaging the total tumor volume in each group. BAL differential cells were counted to analyze inflammatory cells. Results: Cellular growth and colony-forming were promoted by exposure to CSE, and significantly inhibited by S100A8/9 and RAGE-siRNA transfection, especially in A549 cells than BEAS-2B. Cell migration, invasion, MMP-2/9 activities, and the mRNA and protein expression of TLR4, NF-κB, RAGE, S100A8/9 and HMBG1 were higher in CSE exposed A549 cells. S100A8/9 and RAGE-siRNA transfection attenuated those expression, significantly. B(a)P induced an average tumor volume 7.28 mm3 per mouse, and CSE significantly increased tumor volume (8.10 mm3) compared to the B(a)P group. The total cell number and lymphocytes in BAL fluids tended to increase after CSE administration in lung cancer mouse group. Moreover, CSE significantly induced the levels of S100A8/9 and RAGE, p38 and p-ERK, and decreased JNK in serum and tumors with adjacent lung tissues (p &amp;lt; 0.05). Conclusions: We identified cigarette smoke-induced S100A8/A9-RAGE pathway promoted airway inflammation and lung carcinogenesis in vitro and in vivo. Although S100A8/A9 protein contributes to many types of disease, this study will help us gain a better understanding of the complexities of cancer progression. Further studies are needed for therapeutic target of cigarette smoke-induced inflammation and immunosuppression in tumor microenviornment. Citation Format: Hye Seon Kang, In Kyoung Kim, Chang Dong Yeo, Jin Woo Kim, Sang Haak Lee. S100A8/A9-RAGE pathway and chronic airway inflammation in cigarette smoke-induced lung carcinogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3947.
Abstract 3928: Therapeutic targeting of NOTCH1 and neddylation pathway in T cell acute lymphoblastic leukemia
Authors: Carla Bertulfo, Pablo Perez-Duran, Teresa Palomero, Adolfo Ferrando
Journal: Cancer Research (2023)

Abstract T-cell Acute Lymphoblastic Leukemia (T-ALL) is hematologic tumor characterized by the diffuse infiltration of the bone marrow by malignant hematopoietic cells expressing immature T cell markers. Although T-ALL currently has better cure rates primarily due to multiagent or intensified chemotherapy, the prognosis for patients who are resistant or develop relapse to therapy remains very poor. Aberrant Notch homolog-1 (NOTCH1) signaling is a major driver of T-ALL pathogenesis as more than 60% of T-ALL cases harbor activating mutations in the NOTCH1 gene. Gamma Secretase Inhibitors (GSIs) which effectively block the activation of oncogenic protein NOTCH1 are potential candidates for the treatment of T-ALL. However, the clinical application of GSIs is hampered by severe gastrointestinal toxicity due to the inhibition of NOTCH1 signaling in the gut. Here we demonstrate that combination therapy of GSIs and a small molecule inhibitor of the neddylation pathway circumvents the GSI-induced gut toxicity in vitro and in vivo. Genome-wide CRISPR loss-of-function screen in LS174T adenocarcinoma cells revealed neddylation pathway as a main regulator of massive goblet cell differentiation upon NOTCH1 inhibition. Genetic and pharmacologic inhibition of the neddylation pathway in LS174T cells rescued GSI-induced differentiation and cell death. Mechanistically, neddylation inhibition increases the protein stability of Hairy and enhancer of split-1 (HES1), a known regulator of absorptive and secretory cell fate decisions. Combination treatment of GSI and neddylation inhibitor in C57/BL6 mice showed a profound decrease in the number of goblet cells and maintained HES1 protein levels in the intestinal epithelium compared to GSI treatment alone. Remarkably, combined treatment of GSI and neddylation inhibitor in NOTCH1-induced T-ALL mice showed leukemia regression and improved overall survival without any associated gut toxicity. Overall, these results substantiate the potential of targeting NOTCH1 and neddylation pathway in the treatment of NOTCH1-induced T-ALL. Citation Format: Carla Bertulfo, Pablo Perez-Duran, Teresa Palomero, Adolfo Ferrando. Therapeutic targeting of NOTCH1 and neddylation pathway in T cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3928.